1. Field of the Invention
The present invention is in the fields of medicine, public health, immunology, molecular biology and virology. The present invention provides, inter alia, a composition comprising a virus-like particle (VLP) and at least one antigen, wherein said antigen is a GIP protein or a GIP fragment linked to the VLP respectively.
The invention also provides a method for producing the aforesaid composition. The compositions of this invention are useful in the production of vaccines, in particular, for the prevention and/or treatment of obesity and hereby, in particular, by inducing efficient immune responses, in particular antibody responses. Furthermore, the compositions of the invention are particularly useful to efficiently induce self-specific immune responses within the indicated context.
2. Related Art
Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) is a gastrointestinal hormone that is released during a meal from endocrine K-cells that line the gut wall. The amount of GIP that is released into the blood is largely dependent on meal content and is induced primarily by the absorption of ingested fat, glucose or amino acids (Elliott, R. M: et al, (1993), J. Endocrinol. 138, 159-166, Lardinois, C. K. et al, (1988), J Am Coll Nutr. 7(3), 241-7). GIP acts rapidly on pancreatic β-cells to stimulate the release of insulin, thereby ensuring prompt insulin-mediated uptake of glucose into tissues (Dupré J. et al, (1973) J. Clin. Endocrinol. Metab. 37, 826-828). GIP achieves this effect by binding to a seven-transmembrane G-protein-coupled receptor expressed on β-cells. Once bound by GIP, these receptors activate adenylyl cyclase and other signal transduction pathways, ultimately leading to the elevation of intracellular Ca2+ concentrations and insulin exocytosis (Lu, M. et al, (1993), Encocrinology 133, 2861-2870). In addition to fat and glucose intake, ingestion of carbohydrates also stimulates GIP release (Elliott, R. M: et al, (1993), J. Endocrinol. 138, 159-166).
GIP is considered to be one of the principle incretin factors of the entero-insular axis. It has been described that anti-GIP antibodies block the action of GIP on glucose induced insulin secretion (Ebert et al, Endocrinology (1982) 111: 1601). Moreover, GIP has also been postulated to act directly on adipocytes, which express the GIP receptor (Yip et al, Endocrinology (1998) 139: 4004).
Due to its insulinotropic activity, there has been considerable interest in utilising the hormone as a potential therapy for type 2 diabetes (EP171465, WO03/030946). Furthermore, it has recently been shown that GIP receptor knock-out mice (GIPR−/−) have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR−/− mice because of the lack of such enhancement. Accordingly, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes (Miyawaki K. et al, (1999) PNAS 96:26, 14843-14847).
The same research group later showed that wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (GIPR−/−) fed a high-fat diet were protected from both the development of obesity and insulin resistance (Miyawaki K. et al, (2002) Nature Medicine 8: 7, 738-742). However, several studies have observed impaired insulin secretion and hyperglycemia in rodents following nutrient ingestion when GIP action is acutely disrupted with GIP receptor antagonists (Lewis, J. T. et al (2000), Endocrinology 141, 3710-3716; Tseng, C. C. et al (1996) J. Clin. Invest. 98, 2440-2445). This suggests that chronic treatment with a GIP receptor antagonist might result in glucose intolerance, or even in diabetes (Kieffer, T. J. (2003), Trends in Pharmacological Sciences Vol. 24 No. 3, 110-112).